In the preceding period, the program project has shown that deficiency in She proteins strongly alters metabolism, decreases adiposity and increases survival on a high-fat diet, and increases stress resistance and median longevity on a calorie-restricted (CR) diet. The metabolic shift in She-deficient mice strongly resembles that observed in CR animals, and consistently. She expression is decreased in fasting animals. Thus, She-deficiency appears to be a CR-mimetic. In both Shc-deflcient and CR mice there is increased capacity for fatty acid oxidation, ketogenesis, ketone body catabolism, gluconeogenesis, and amino acid catabolism, while capacity for glycolysis is decreased. She mutant mice have decreased She levels as a consequence of mutation, and CR also causes decreased levels of She proteins. She proteins may play an important role in transitioning from the fed to fasted state. In particular, the program will pursue the hypothesis that decreases in She proteins in tissues, such as skeletal muscle and liver, are needed for animals to properly adapt to dietary conditions which require a sustained increase in fatty acid oxidation (CR, low-carbohydrate diets, high-fat/high-carbohydrate diets, etc.), and it is under these conditions that the influence of Shc on lifespan is most noticeable. Thus, the aims of this project are focused on determining the influence of She proteins on the metabolic response to high-fat/high-carbohydrate diets, the role She based modifications play in the metabolic response to CR, and whether or not a diet (low-carbohydrate) that induces chronic increases in capacity for P-oxidation, ketone body metabolism and gluconeogenesis can mirror the effects of CR and decreased She levels. The three Specific Aims of this subproject are to (1) determine the mechanism for resistance to weight gain in p66Shc-/- mice on a high-fat/high-carbohydrate diet; (2) determine if low-carbohydrate the metabolic response to sustained CR is altered in p66Shc-/- mice; and (3) determine diets can mimic the metabolic changes observed in the p66Shc-/- mice and increase life span. The proposed studies will provide new information about the influence of She proteins on energy metabolism and life oxidation. span in animals consuming diets which require sustained increases in fatty acid oxidation.